As methods of administration of drugs, a variety of methods such as oral administration, intrarectal administration, intradermal administration, intravenous administration and the like have been known. Among them, the oral administration have been adopted widely. However, the oral administration had disadvantages i.e. that drugs are easily subject to primary metabolism in liver after absorption of the drug, and that an excess high blood concentration of drug is recognized temporally after administration. In addition, many side effects such as disturbance in gastrointestinal tracts, nausea, loss of appetite and the like have been reported in case of oral administration.
Therefore, in order to dissolve the disadvantages in association with the oral administration, the percutaneous administration method which can be expected to make absorb drugs safety and continuously, is being watched in recent years. The formulations for percutaneous administration have been developed already, and the products are on the market.
However, the percutaneous absorbability of drugs by means of the formulations for percutaneous administration are yet insufficient, and the objects are not deemed to be attained sufficiently. Namely, with the bases by itself which are used in the normal formulation for percutaneous administration, a sufficient percutaneous absorption of the formulated pharmaceutical components can not be easily attained in many cases, since normal skins have a barrier function to avoid invasions of foreign materials into body.
Thus a means to control the permeation of drugs via stratum corneum of skins and to increase the percutaneous absorbability of drugs, have been needed, and the formulation of so-called transdermal absorption enhancer in base has been attempted generally. For examples, as an absorption enhancer combining lower alkyl amide, dimethylacetamide and ethyl alcohol, isopropyl alcohol, isopropyl palmitate and the like (U.S. Pat. No. 3,472,931), an example of combination of 2-pyrrolidone and an appropriate oil, and straight-chain fatty acid and alcohol ester (U.S. Pat. No. 4,017,641), an example of lower alcohol and C.sub.7 -C.sub.20 alcohol, C.sub.5 -C.sub.30 aliphatic hydrocarbon, alcohol ester of C.sub.19 -C.sub.26 aliphatic carboxylic acid, C.sub.10 -C.sub.24 mono or dieter, C.sub.11 -C.sub.15 ketone and water (JP A 61-249934) and the like have been proposed. However, these conventional absorption enhancers and absorption enhancing compositions can not be deemed to be sufficiently safe to skins yet.
Further, as an example of compositions of formulations for percutaneous administration, a combination of a drug and an organic acid have been reported. For examples, a tape formulation in which a combination of betamethasone valerate and an organic acid is formulated in a natural rubber pressure sensitive adhesive (JP A 56-61312), a tape formulation in which a combination of a non-steroid antiinflammatory analgesic and an organic acid is formulated in an acrylic pressure sensitive adhesive (JP A 62-126119), a pap type formulation in which a combination of methyl salicylate as a pharmaceutical component, an emulsifying agent, an organic acid, a plasticizer, a tackifying resin and water is formulated in a styrene-isoprene-styrene block copolymer (JP A 63-159315) and the like have been proposed.
However, the objects of usages of the organic acids in these examples are to improve the stability and solubility, and to control pH and the like. In addition, since these drugs are acid or neutral, these formulations are not intended to improve sufficient percutaneous permeation of the physiological substance via ion-pair formations with organic acid.
Further, there have been attempts to improve the percutaneous permeable property of basic physiological active substance. For example, a tape formulation in which a combination of citric acid and isopreterenol hydrochloride is formulated in an acrylic pressure sensitive adhesive (JP A 63-79820), a tape formulation in which a combination of an organic acid and vinpocetine is formulated in an acrylic pressure sensitive adhesive (JP A 5-25039) and the like have been reported. However, these formulations have a problems of irritation at the time of releasing, and the amount of released drug is too few to provide sufficient effects on treatment.
Thus, the present invention was made in order to dissolve the problems in relation to the prior arts, and the object of the present invention is to provide a matrix type patch formulation which increases percutaneous absorbability of the physiological active substance and is extremely reduced in irritation to skins where the formulation is applied.